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International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Contains fulltext : 229474.pdf (Publisher’s version ) (Open Access) Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.

Unexplained childhood fracture(s) warrant consideration of physical abuse and osteogenesis imperfecta (OI). Genetic OI testing may identify “variants of unknown significance (VUS).” Interpretation of VUS in context of potential abuse may have protective, criminal, and medical impacts. This case series explores practices regarding clinicians' interpretation of VUS during child abuse evaluations. Variability was noted regarding factors considered for interpreting clinical significance. Based on these cases, recommendations for careful and thorough evaluation are detailed, including proposed use of a limited follow-up skeletal survey in 3 months, as a consideration to assess healing of prior fractures and to look for any additional injuries.

Urea cycle disorders (UCD) are rare inborn errors of metabolism which result from mutations in the genes encoding for one of six enzymes or two transporters necessary for normal function of the urea cycle and are characterized by hyperammonemia and life-threatening hyperammonemic crises1,2. Hyperammonemia-related neurologic injury ranges from lethal cerebral edema to mild or subclinical cognitive impairment among individuals with milder genetic defects3. Abnormalities in executive function, manifested by difficulty in goal setting, planning, monitoring progress and purposeful problem solving significantly impair day-to-day function among children with UCDs, even those with milder disease who present beyond the neonatal period4. Management of UCD patients typically involves dietary protein restriction, dietary supplements and, when dietary management alone is insufficient, sodium phenylbutyrate (NaPBA), which is the only approved drug (Ucyclyd Pharma, US trade name: BUPHENYL®, EU: AMMONAPS®) for treatment of UCDs2,5. Glycerol phenylbutyrate is an investigational agent being developed for UCDs 6,7,8. Like NaPBA, it contains phenylbutyric acid (PBA), a pro-drug that is converted via β-oxidation to the active moiety, phenylacetic acid (PAA), which conjugates with glutamine to form phenylacetylglutamine (PAGN). PAGN is excreted in the urine and mediates waste nitrogen excretion. Unlike NaPBA, glycerol phenylbutyrate consists of three molecules of PBA joined to glycerol in ester linkage that is hydrolyzed in the small intestine by pancreatic lipases to release PBA, contains no sodium, has minimal taste and no odor, and 17.4 mL contains the same amount of PBA as 40 tablets of NaPBA, the maximal approved daily dose 6,7,8. The development of glycerol phenylbutyrate for UCD, rare disorders with fewer than 500 patients in the US currently estimated to be treated with NaPBA, has involved a cooperative effort among investigators of the NIH-funded UCD Consortium, the National Urea Cycle Disorders Foundation and Hyperion Therapeutics 2,9,10. This report describes the results of the pivotal phase 3 study of glycerol phenylbutyrate for UCD, as well as short and long-term ammonia control and neurocognitive outcomes among a total of 91 UCD patients participating in four clinical trials.